DESCRIPTION: (adapted from the abstract) The overall objective of the proposal is to identify the pathophysiologic basis for the insulin resistance seen in essential hypertension using the spontaneously hypertensive rat (SHR) as a model. The basis for the hypothesis underlying this grant proposal is that insulin resistance in hypertension may be due to increased tissue generation of angiotensin II (AII). In 70 percent of essential hypertensives, blood pressure is either wholly (high renin hypertension) or partly (normal or medium renin hypertension) AII dependent. In SHR, increased AII generation occurs as a result of an abnormality that has been termed, "non-modulation" of the renin-angiotensin axis (RA axis). AII could affect insulin sensitivity as a result of its suppressive effect on glycogen synthesis and/or a reduction in skeletal muscle glucose uptake through vasoconstriction. The experimental design proposes four specific aims that comprise the overall objective. First, the relative contributions of abnormal hepatic and skeletal muscle glucose handling to overall insulin resistance will be identified using radioisotopic glucose turnover studies and the glucose clamp technique. Second, the effect of exogenous AII on glucose turnover will be assessed by administering AII with and without a specific AII antagonist, or an ACE inhibitor. Third, the role of endogenous AII generation will be studied by assessing insulin sensitivity during interventions designed to stimulate and suppress the RA axis, such as varying salt intake, and a variety of drugs, Finally, the mechanism for insulin resistance in SHR will be explored, using tracer methods for assessing cellular glucose uptake and glycogen synthesis in skeletal muscle and liver in vivo, as well as by measuring in vitro the activities of glycogen synthase and the specific synthase kinase which is affected by AII in liver and skeletal muscle. These studies will be performed under the conditions outlined in steps 1-3 to determine the cellular basis for insulin resistance in SHR and identify the role, if any, of AII in the process.